The present invention relates to novel derivatives of 2'-deoxyuridine substituted in the 5-, 3'- or 5'-position by a .alpha.-aminoacyl groups, to a process for their preparation and to pharmaceutical compositions in which they are present.
Some 2'-deoxyuridine derivatives are already known.
Thus derivatives of 2'-deoxyuridine substituted in the 5-position have been described which have the following general chemical formula: ##STR2## in which R is an alkyl or alkenyl radical having from 1 to 4 carbon atoms, an aryl radical or a halogen, it being possible for said alkyl and aryl radicals to contain at least one halogen substituent.
5'-Amino-2', 5'-dideoxy-5-methyluridine of the formula:
is also known, especially from U.S. Pat. No. 4,093,716; it is presented as a potential inhibitor of the herpes virus. The preparation of this compound is described in an article by Horwitz et al. in the journal "J. Org. Chem." 27 3045, (1962).
3'-Amino-2',3'-dideoxy-5-methyluridine of the formula: ##STR3## is also known, especially from a publication by LIN and PRUSOFF (J. Med. Chem. 21 109 (1978)).
Finally, 5-amino-2'-deoxyuridine of the formula: ##STR4## is known, especially from a publication by BELTZ and VISSER (J. Biol. Chem., 226, 1035, (1957)). The document J. Med. Chem. 1979, vol. 22, No. 6, pages 621 to 631 describes in general terms a process for the preparation of 5-[[.omega.-(iodoacetamido)acyl]amino]-2'-deoxyuridines using, as synthesis intermediates, compounds of the formula: ##STR5## in which R is the residue of an .omega.-amino acid.
These compounds are not presented as being capable of therapeutic application.
The present invention relates to a novel class of derivatives of 2'-deoxyuridine substituted in the 5-, 3'- or 5'-position by .alpha.-aminoacyl groups, which have the following general formula: ##STR6##
in which
R is selected from an alkyl or alkenyl radical having from 1 to 4 carbon atoms, an aryl radical or a halogen, it being possible for said alkyl, alkenyl and aryl radicals to contain at least one halogen substituent, and a radical of the formula --NH--R.sub.1, in which R.sub.1 is an amino acid residue or a peptide residue containing from 2 to 6 amino acids; and PA0 R' and R" are selected from a hydroxyl radical and a radical of the formula --NH--R.sub.1, in which R.sub.1 is as defined above, PA0 R'.sub.a and R".sub.a are selected from a hydroxyl radical and a radical --NH.sub.2,
with the proviso that R' and R" are not simultaneously --NH--R.sub.1 and that, when R is --NH--R.sub.1, R' and R" are simultaneously a hydroxyl group, and to their pharmaceutically acceptable salts.
The scope of the invention also includes all the possible optical isomers of the compounds of formula (I) and mixtures thereof.
In general formula (I), a halogen atom is preferably a chlorine or bromine atom.
The alkyl and alkenyl groups can be groups with a linear or branched chain.
An alkyl group having from 1 to 4 carbon atoms is, for example, a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl group, preferably a methyl or ethyl group.
An alkenyl group having from 1 to 4 carbon atoms is, for example, a vinyl, propenyl or butenyl group, preferably a vinyl group.
The pharmaceutically acceptable salts of the compounds of formula (I) include those formed with a mineral acid, for example hydrochloric acid or sulfuric acid, or with an organic acid, for example citric, tartaric, malic, maleic or fumaric acid.
It has been discovered, totally surprisingly, that these novel derivatives possess the valuable pharmacological property of being inhibitors of the fetal thymidine kinase present in human cancerous tissues and are thus inhibitors of DNA synthesis in proliferating cancerous cells.
According to one particular characteristic, the invention relates to the novel class of derivatives of 2'-deoxyuridine substituted in the 5'-position, i.e. the compounds of general formula (I) in which R' is a hydroxyl group and R" is a group --NH--R.sub.1.
According to another particular characteristic, the invention relates to the novel class of derivatives of 2'-deoxyuridine substituted in the 3'-position, i.e. the compounds of general formula (I) in which R' is a group --NH--R.sub.1 and R" is a hydroxyl group.
According to yet another particular characteristic, the invention relates to the novel class of derivatives of 2'-deoxyuridine substituted in the 5-position, i.e. the compounds of general formula (I) in which R is a group --NH--R.sub.1 and R' and R" are simultaneously hydroxyl groups.
Depending on the structure of the amino acid or peptide mentioned above, the novel compounds of formula (I) according to the invention are in the D, L or DL foam.
The general process for the preparation of the compounds according to the invention of general formula (I) as defined above comprises reacting an amine derivative of the general formula: ##STR7## in which R.sub.a is selected from an alkyl or alkenyl radical having from 1 to 4 carbon atoms, an aryl radical or a halogen, it being possible for said alkyl, alkenyl and aryl radicals to contain at least one halogen substituent, and a radical --NH.sub.2 ; and
with the proviso that R'.sub.a and R".sub.a are not simultaneously --NH.sub.2 and that, when R.sub.a is --NH.sub.2, R'.sub.a and R".sub.a are simultaneously a hydroxyl group,
with an amino acid or a peptide containing from 2 to 6 amino acids, by an enzymatic or chemical method, and, if desired, converting a compound obtained in this way into a pharmaceutically acceptable salt.
The compounds of L form are preferably prepared by enzymatic reaction of the amine derivatives of formula (Ia) with an amino acid or a peptide of L or DL form, in the presence of an enzyme selected from papain and chymopapain, the reaction being carried out at a temperature of about 10.degree. to about 70.degree. C. in an acid medium. Under these conditions, a reaction takes place between the amine group of the amine derivative in the 5-, 3'- or 5'-position and the free acid group of the amino acid or peptide, it being understood that the amine groups of said amino acid or peptide have been blocked beforehand with known reagents such as benzyloxycarbonyl, paramethoxybenzyloxycarbonyl, t-butoxycarbonyl or fluorenomethoxycarbonyl.
The compounds of L, D or DL form can also be prepared using a purely chemical process, which may involve the separation of a mixture of isomers of the compounds of formula (I) into the isolated isomers.
Surprisingly, the compounds of formula (I) according to the invention were found to be active in inhibiting DNA synthesis in cancerous cells and certain viral particles.
These compounds are therefore especially useful in the treatment of hormone-dependent cancers and infections of viral origin.
Oral administration is generally employed for all conditions requiring such compounds. For this purpose, the compounds of the invention can be administered at doses for example of between about 30 mg/m.sup.2 and about 100 mg/m.sup.2 per day in the treatment of cancers and for example of between about 50 mg/kg and about 250 mg/kg per day in the treatment of infections of viral origin. Of course, these dosages can be adjusted to ensure the optimum therapeutic response.
Thus, according to a final feature, the present invention relates to pharmaceutical compositions, especially those active as inhibitors of DNA synthesis in proliferating cancerous cells, which contain, as the active ingredient, at least one of the above-defined compounds of general formula I in association with a pharmaceutically acceptable, non-toxic vehicle or carrier.
The pharmaceutical compositions of the invention are generally prepared by conventional processes and are administered in an appropriate pharmaceutical form; for example, a solid oral form can contain, together with the active compound, diluents, for example lactose or cellulose; lubricants, for example stearic acid or polyethylene glycols; binders such as starches or methyl cellulose; colorants; sweeteners; wetting agents such as, for example, polysorbates; and, in general, non-toxic and pharmacologically inert substances used in pharmaceutical compositions.
The invention will be illustrated in greater detail by the following non-limiting Examples: